tbuckley/cabot-search huggingface dataset:
DDDR-05. TARGETED INHIBITION OF DNA REPAIR AND SURVIVAL SIGNALING IN DIFFUSE INTRINSIC PONTINE GLIOMAS
Authors: Ivana Barravecchia, Monika Sharma, Robert Teis, Jeanette Cruz, Rachel Mumby, Elizabeth Ziemke, Carlos Espinoza, Varunkumar Krishnamoorthy, Brian Magnuson, Mats Ljungman, Carl Koschmann, Christopher Whitehead, Judith Sebolt-Leopold, Stefanie Galban
Journal: Neuro-Oncology (2023)

Abstract Therapeutic resistance remains a major obstacle to successful clinical management of Diffuse Intrinsic Pontine Glioma (DIPG), a high-grade pediatric tumor of the brain stem. In nearly all patients, available therapies fail to prevent progression. Innovative combinatorial therapies that penetrate the blood-brain barrier and lead to long-term control of tumor growth are desperately needed. We identified mechanisms of resistance to radiotherapy, the standard of care for DIPG. Based on these findings, we rationally designed a brain-penetrant small molecule, MTX-241F, that is a highly selective inhibitor of EGFR and PI3 kinase family members, including the DNA repair protein DNA-PK. Preliminary studies demonstrate that micromolar levels of this inhibitor can be achieved in murine brain tissue and that MTX-241F exhibits promising single-agent efficacy and radiosensitizing activity in patient-derived DIPG neurospheres. Its physiochemical properties include high exposure in the brain, indicating excellent brain penetrance. Since radiotherapy results in double-strand breaks that are repaired by homologous recombination (HR) and non-homologous DNA end joining (NHEJ), we have tested the combination of MTX-241F with an inhibitor of ATM to achieve blockade of HR and NHEJ, respectively, with or without radiotherapy. When HR blockers were combined with MTX-241F and radiotherapy, synthetic lethality was observed, providing impetus to explore this combination in clinically relevant models of DIPG. Our data provide proof-of-concept evidence to support advanced development of MTX-241F for the treatment of DIPG. Future studies will be designed to inform rapid clinical translation to ultimately impact patients diagnosed with this devastating disease.
EPCO-13. CNMF-SNS, A FRAMEWORK FOR UNSUPERVISED INTEGRATION OF MULTIOMICS DATA, IDENTIFIES INVASION AND RECURRENCE ASSOCIATED PROGRAMS IN GBM
Authors: Theodore Verhey, Heewon Seo, Sorana Morrissy
Journal: Neuro-Oncology (2023)

Abstract Glioblastoma (GBM) is an aggressive cancer of the brain for which novel therapies are urgently needed. Heterogeneity in GBM underlies tumor evolution and resistance to therapy and involves genetic diversity of tumor cells, spatially distinct niches harbouring stem-like cells, and immune cells spanning anti- and pro-tumor states. No single profiling methodology can capture all these facets of tumor biology in the same space and time, necessitating multi-omics data collection and computational methods suited for multi-omic integration across and within cohorts. We therefore set out to develop a generalizable framework for integration that can bridge across cohorts and data types. Using consensus non-negative matrix factorization (cNMF), we discover gene expression programs (GEPs) corresponding to cell types and/or states in an unsupervised fashion. Rather than choosing a single rank (number of programs), we identify both high and low-resolution programs for each dataset, and then integrate programs from all datasets and ranks into a solution network space (SNS) on which graph algorithms identify communities of highly similar GEPs identified in all or some datasets. These communities are characterized by gene set enrichment analyses and association with sample metadata. SNS communities can be used to transfer sample metadata across datasets, enabling multi-omics and multi-cohort integration, even in the absence of shared samples or cells. We showcase the utility of cNMF-SNS in integrating multiomics datasets of GBM from single-cell to bulk RNA-Seq and mass spectrometry proteomics. We further demonstrate the power of cNMF-SNS to define and cross-annotate programs identified in 5 complementary mass spectrometry datasets of GBM, layering on survival, driver gene mutation status, clinical features, and imaging features. We demonstrate robust mapping of biologically and clinically relevant processes, highlighting how programs for tumor cell invasion and therapy resistance can be mined for novel therapeutic targets. cNMF-SNS is available at https://github.com/MorrissyLab/cNMF-SNS.
TMIC-08. CLAUDIN-1 UPREGULATION IN GLIOBLASTOMA INDUCED BLOOD-BRAIN-BARRIER DYSFUNCTION VIA A PARACRINE MECHANISM
Authors: Brittany Schweiger, Forrest Kievit
Journal: Neuro-Oncology (2023)

Abstract BACKGROUND Blood-brain-barrier (BBB) disruption is a well-known phenomenon in glioblastoma. However, the mechanism driving BBB dysfunction in GBM is still unknown, especially in the previously established vasculature near the invasive edge. In this study, we aimed to determine if GBM paracrine signaling is sufficient to induce BBB dysfunction and identify changes in the tight junctions of the BBB. METHODS An in vivo xenograft model was established through an intracranial injection of U-87 MG cells in nude mice. Weekly MRIs were performed to monitor tumor growth. Two weeks after tumor appearance, brains were collected following a 4% PFA perfusion for immunostaining and confocal imaging. An in vitro model of the BBB was created by seeding primary mouse brain microvascular endothelial cells (BMECs) on transwell inserts. Once the BMECs reached confluency with a TEER value of 170-175Ω*cm2, the media was replaced with filtered conditioned media from U-87 MG cell line, an IDH mutant cell line, or BMECs for three days with TEER values monitored each day. RESULTS Immunofluorescent staining revealed a significant increase in claudin-1 expression and decrease in claudin-5 expression in the tumor vs normal brain tissue of our in vivo model (p &amp;lt; 0.01). After 24 hours of exposure to conditioned media from both U-87 MG and IDH mutant cells, BMECs had a significant decrease in TEER compared to control and BMEC conditioned media (p &amp;lt; .0001). After 72 hours, TEER values continued to decrease, reaching around 155Ω*cm2, with control BMECs remaining around 187Ω*cm2. CONCLUSIONS These results suggest GBM cells secrete factors capable of inducing changes in the tight junction proteins of the BBB and increasing its permeability. Future studies will aim to identify the mechanism in which these changes occur.
BIOM-53. MENINGIOMA COPY NUMBER VARIANT THRESHOLDS REVEAL OPTIMAL SIZES FOR GAINS OR LOSSES THAT PREDICT LOCAL FREEDOM FROM RECURRENCE OR OVERALL SURVIVA
Authors: Minh Nguyen, William Chen, Abrar Choudhury, Stephen Magill, David Raleigh
Journal: Neuro-Oncology (2023)

Abstract INTRODUCTION Meningiomas demonstrate heterogeneous rates of postoperative local freedom from recurrence (LFFR) and overall survival (OS). Risk-stratification models incorporating copy number variants (CNVs) improve outcome prediction, but optimal size thresholds for defining CNVs in meningiomas are unknown, and previous models have used thresholds ranging from 5-80% that are applied uniformly across all chromosome arms. Here we show that optimizing chromosome-specific CNV size thresholds improves meningioma risk-stratification. METHODS 565 retrospective meningiomas with clinical data and DNA methylation profiles from 2 international institutions were included. CNVs were defined from DNA methylation profiles using iterative thresholds ranging from 5-95% for each chromosome arm. The area under the curve (AUC) for 5-year LFFR or OS was calculated using CNVs across iterative thresholds for each chromosome arm. LASSO and Elastic Net Cox regressions were used to generate multi-CNV models for LFFR or OS. RESULTS AUC for LFFR or OS peaked with CNV thresholds that were unique to each chromosome arm. Chromosome 1p deletion had optimal AUCs for LFFR and OS of 0.72 and 0.70 at thresholds of 40% and 30%, respectively. Chromosome 1q amplification had optimal AUCs for LFFR and OS of 0.58 and 0.60 at thresholds of 25% and 20%, respectively. Two previously published CNV-based risk-stratification models (integrated score and integrated grade, optimal LFFR thresholds of 5% and 20%, AUCs of 0.77 and 0.78, respectively) demonstrated heterogeneous sensitivity to CNV thresholds. LASSO and Elastic Net Cox regression identified size-dependent risk-stratification models incorporating loss of 1p, 3q, 4p, 5p/q, 6p/q, 9p, 10q, 11p, 12q, 13q, 14q, 17q, and 18p/q, and gain of 1q, 9q, 10p, and 17q. The optimal AUCs for LFFR and OS from multi-CNV models were 0.77 and 0.77 at thresholds of 25% and 35%, respectively. CONCLUSIONS Interrogating CNV thresholds reveals optimal chromosome-specific CNV sizes for predicting LFFR and OS.
IMMU-45. REVERSIBLE PARKINSONISM AFTER BCMA-DIRECTED CAR T CELL ADMINISTRATION
Authors: Alexandra Gewirtz, Sham Mailankody, Saad Usmani, Bianca Santomasso
Journal: Neuro-Oncology (2023)

Abstract B-cell maturation antigen (BCMA)-targeting chimeric antigen receptor (CAR)T cell therapy has revolutionized the treatment of patients with relapsed or refractory multiple myeloma (MM), resulting in FDA-approval of two products, idecabtagene vicleucel (ide-cel) and ciltacabtagene autoleucel (cilta-cel). In addition to immune effector cell associated neurotoxicity syndrome (ICANS), a novel hypokinetic movement disorder resembling parkinsonism has been reported with BCMA-targeting CAR. Cases reported to date have been irreversible or fatal, and guidance on how to manage this complication is limited. Here we describe a patient with MM who developed features of parkinsonism on day 24 post ide-cel infusion which were apparently reversible with supportive care and dexamethasone. A 77 year-old man with MM received standard lymphodepletion followed by ide-cel. He developed grade 1 cytokine release syndrome (CRS) for which he received tociluzumab, followed by transient expressive aphasia (grade 2 ICANS) on day 23. Brain MRI showed no structural abnormality. On day 24 he developed new tremor and gait impairment. Neurologic examination revealed cogwheeling in bilateral wrists, hypomimia, soft speech, and slowed gait. Lumbar puncture and electroencephalogram were unremarkable. FDG-PET brain did not show basal ganglia hypometabolism or abnormal avidity. Lymphocyte percentage was elevated and correlated with a high level of circulating CAR+ T cells. He was started on dexamethasone 10 mg q day, receiving a total of 17 days of steroids with improvement in symptoms. At day 60, ambulation was improved and cogwheeling and hypomimia resolved. By day 90, all neurological symptoms had resolved. Improvement remained sustained as of last follow up day 120. To our knowledge, this is the first case report of steroid responsive parkinsonism after BCMA-CAR therapy. Our report supports close neurological monitoring of patients beyond 30 days after BCMA-CAR and suggests that intervening early in the setting of hypokinetic movement disorders may lead to sustained reversal of symptoms.
PATH-26. A RARE CASE OF EXOPHYTIC PILOCYTIC ASTROCYTOMA DIAGNOSED VIA MOLECULAR TESTING
Authors: Michelle Chee, Tresa McGranahan
Journal: Neuro-Oncology (2023)

Abstract INTRODUCTION Pilocytic astrocytoma (PA) is a WHO grade 1 neoplasm that can share histological and radiological features with more malignant entities, including high grade astrocytoma with piloid features. In cases where the differential remains broad after histopathological examination, DNA methylation analysis and next generation sequencing can contribute significantly to making an accurate diagnosis. Machine learning has also played a role in developing multiple classifying algorithms which group tumors by their methylation status. CASE We report a case of an exophytic left frontal mass with adjacent bone erosion that preoperatively was favored to be a meningioma. Intraoperatively, the mass was found to be cortically based. With histopathologic review at two centers, the diagnosis remained IDH wildtype low-grade glioma not otherwise specified. The clinical treatment team interpreted the post-operative increase in T2 signal as radiographic progression consistent with high grade glioma and planned to proceed with chemoradiation. Patient elected for further evaluation; methylation array profiling and next generation sequencing identified a KIAA1549::BRAF fusion, consistent with a final diagnosis of pilocytic astrocytoma, a WHO Grade 1 Glioma. Given the favorable prognosis following gross total resection, the patient was recommended active surveillance and radiation and chemotherapy treatment planning was stopped. DISCUSSION This is a rare case of an exophytic pilocytic astrocytoma in which the tumor’s atypical histologic and radiographic appearance increased the likelihood of diagnostic errors. This case illustrates the clinical importance of utilizing methylation array profiling and next-generation sequencing to confirm a diagnosis.
BIOM-22. CLINICAL ASSESSMENT OF SIGNALING PATHWAY ACTIVITY IN GLIOMA
Authors: Sol Beccari, Viva Voong, Shawn Hervey-Jumper, Mitchel Berger, Joanna Phillips
Journal: Neuro-Oncology (2023)

Abstract Despite advances in our understanding of tumor biology, many targeted therapies for diffuse glioma have failed without an understanding of why. Improved patient stratification and assessment of biologic activity in window of opportunity clinical trials will address this failure. The clinically validated, robust biomarkers available, however, are limited. Moreover, evidence-based criteria for biospecimen acquisition are lacking. To address this need we investigated the preanalytic variables that impact the assessment of PI3K/AKT/mTOR and MAPK signaling activity at single cell resolution. To replicate the conditions in window of opportunity clinical trials, tumor tissue from a murine model for glioblastoma (GBM) was utilized and the impact of cold ischemia time (CIT), slide storage duration and temperature on detection of key phospho-proteins was determined. We then validated our findings using human glioma samples acquired in the operating room. To assess the PI3K/AKT/mTOR signaling, phosphorylation of proteins at three nodes of the pathway were investigated. Phosphorylated-PRAS40 (p-PRAS40) is upstream of mTOR and phosphorylated-RPS6 (p-RPS6) and phosphorylated-4EBP1 (p-4EBP1) are downstream of mTOR. Detection of cells expressing p-RPS6 was the most robust with no significant alterations up to 6hrs cold ischemia time (CIT). p-4EBP1 signal was unaltered up to 20min CIT, however, decreased at 2h and 6h (p&amp;lt; 0.001). The detection of p-PRAS40 was variable at 20min and showed a decreased tendency at 2h and 6h. For p-RPS6, p-4EBP1, and p-PRAS40 the assessment of protein intensity per cell was highly variable at all time points analyzed (p&amp;lt; 0.05 at 20min, 2h, and 6h). Thus, for assessment of the PI3K/AKT/mTOR pathway in diffuse glioma using clinical samples, the detection of p-RPS6 is the most stable when time elapsed between sample acquisition and downstream processing (CIT) is long, while p-4EBP1 requires short (≤20 min) delays and p-PRAS40 is more variable.
TMET-05. LIPOPHAGY CONTROLS CHOLESTEROL HOMEOSTASIS AND BRAIN TUMOR GROWTH
Authors: Feng Geng, Yaogang Zhong, Huali Su, Etienne Lefai, William Yong, Arnab Chakravarti, Deliang Guo
Journal: Neuro-Oncology (2023)

Abstract Cholesterol is an essential structural component of cell membranes. How rapidly growing tumor cells maintain membrane cholesterol homeostasis is poorly understood. Here, we found that glioblastoma (GBM), the most lethal brain tumor, maintains normal levels of membrane cholesterol, but with an abundant presence of cholesteryl esters (CEs) in their lipid droplets (LDs). Mechanistically, we found that SREBP-1, a master transcription factor that is activated upon cholesterol depletion, upregulates critical autophagic genes, including ATG9B, ATG4A and LC3B, as well as lysosome cholesterol transporter NPC2. This upregulation promotes LD lipophagy, resulting in the hydrolysis of CEs and the liberation of cholesterol from the lysosomes, thus maintaining plasma membrane cholesterol homeostasis. When this pathway is blocked GBM cells became quite sensitive to cholesterol deficiency with poor growth. Our study unravels a previously unrecognized SREBP-1-autophagy-LD-CE hydrolysis pathway that plays an important role in maintaining membrane cholesterol homeostasis, while providing a potential new therapeutic avenue for GBM
SURG-44. VENTRICULAR CEREBROSPINAL FLUID SAMPLING IN PEDIATRIC DIFFUSE MIDLINE GLIOMA PATIENTS: INSTITUTIONAL EXPERIENCE AND REVIEW OF THE LITERATURE
Authors: Daphne Li, Wendy Stellpflug, Kathleen Romanski, Stacy Speck, Amanda Saratsis
Journal: Neuro-Oncology (2023)

Abstract BACKGROUND Increasing evidence suggests that circulating biomarkers may serve diagnostic and longitudinal monitoring purposes in pediatric neuro-oncology. Mutant tumor DNA is detectable in the cerebrospinal fluid (CSF) of pediatric diffuse midline glioma (DMG) patients and quantity can reflect disease burden. CSF sampling (“liquid biopsy”) via a CSF access device could therefore play a role in DMG management. Therefore, we set to evaluate the incidence of hydrocephalus (HCP) in DMG patients, and to characterize ventricular reservoir placement and access practices. METHODS A single institution retrospective review of DMG patients &amp;lt;21-years-old was performed (1984-2019). MEDLINE searches for reports of ventricular reservoir or shunt placement in DMG, and reservoir access for intraventricular chemotherapy (IVC) were performed. RESULTS At our institution, 62.6% of DMG patients (67/108) required intervention for HCP: 19.4% provided transient CSF access (ETV alone n = 3, EVD n = 8, unspecified n = 2), and 80.6% permanent CSF access (ETV + reservoir n = 13, shunt n = 41). Further, 22/34 patients with initially transient CSF devices required conversion to a permanent device. Five devices were revised for malfunction, one for infection. Seventeen articles cited HCP in 22% to 100% of DMG patients. IVC administration was described in 632 patients (seven articles), with 42 infectious and 63 non-infectious complications. CONCLUSIONS Management of HCP is often necessary in children with DMG. Given the low rate of clinical risk associated with VAD placement and access, and the potential utility of longitudinal disease monitoring via CSF analysis, VAD placement could be considered in future clinical trials to guide DMG treatment.
EPID-06. TARGETED AGENTS IN PATIENTS WITH RECURRENT GLIOBLASTOMA– A SYSTEMATIC META-ANALYSIS OF RANDOMIZED CLINICAL TRIALS
Authors: Franziska Maria Ippen, Angelika Scherm, Tobias Kessler, Peter Hau, Hansjörg Baurecht, Wolfgang Wick, Helge Knüttel, Michael F Leitzmann, Corinna Seliger
Journal: Neuro-Oncology (2023)

Abstract BACKGROUND Glioblastoma (GB) is the most common malignant primary brain tumor in adults and associated with a dismal prognosis. While the standard of care for newly diagnosed GB is defined in current treatment guidelines, recommendations for recurrent GB are less well established. The current systematic meta-analysis of recently published randomized controlled trials (RCTs) represents the strongest available evidence on targeted agents in patients with recurrent GB. METHODS Cochrane Library, Pubmed, MEDLINE (Ovid), ClinicalTrials.gov, WHO's International Clinical Trials Registry Platform and Google Scholar were searched ranging from the year 1954-2022 for RCTs of targeted therapies in patients with recurrent GB. Hazard Ratios (HRs) of overall survival (OS) and progression-free survival (PFS) were extracted to perform a random-effects meta-analysis. RESULTS 16 RCTs (n=3,025 patients) were included in the meta-analysis. Experimental treatment was either compared to lomustine (CCNU) alone, in combination with CCNU/temozolomide (TMZ) to CCNU alone or to bevacizumab alone. In these three subgroups, targeted agents associated with improved OS compared to the control arm were regorafenib (RR= 0.50; 95% CI 0.33-0.75), Depatux- M+ TMZ (RR= 0.66; 95% CI 0.44-0.93) and rindopepimut + bevacizumab (RR= 0.53; 95% CI 0.32-0.88). Treatment with bevacizumab + CCNU (RR= 0.49; 95% CI 0.35-0.69) and regorafenib (RR= 0.65; 95% CI 0.44-0.95) were associated with improved PFS. CONCLUSION In this systematic meta-analysis, we provide the current highest level of evidence for the role of targeted therapies in recurrent GB. Even though some studies revealed a benefit either for OS and/or PFS, results have to be critically reviewed regarding initial distribution of prognostic factors, underlying molecular mechanisms, sample size and trial design. There is a need for more specific and personalized study designs using newly obtained tumor tissue and close monitoring of treatment responses to allow for potential modification of treatment if needed.
CNSC-01. THE ROLE OF SEROTONERGIC RECEPTOR, HTR2B, ON MYELOID DERIVED SUPPRESSOR CELLS IN THE BRAIN METASTATIC ENVIRONMENT
Authors: Mukund Iyer, Diganta Das, Brooke Nakamura, Saman Sedighi, Max Reed, Alexa Pakravan, Priya Shah, Julie Jang, Aaron Baugh, Edgar Gonzalez, Evanthia Roussos Torres, Josh Neman
Journal: Neuro-Oncology (2023)

Abstract In the United States, greater than 12% of cancer patients develop brain metastases (br-mets) and median survival remains an abysmal 4-6 months. Throughout the metastatic cascade, tumor cells attract and reprogram stromal cells, such as myeloid derived suppressor cells (MDSCs), which support cancer growth by promoting tissue remodeling, EMT, invasion, immunosuppression, angiogenesis. Once tumor cells have breached the brain’s CNS defenses, infiltrating immune cells can penetrate the glia limitans and enter the CNS parenchyma to help establish the brain metastatic niche. However, there is scant understanding of MDSC’s contribution to the brain metastatic microenvironment. The brain metastatic environment is particularly unique because CNS-resident cells such as microglia, astrocytes, choroid plexus, and neurons function as local mediators to alter invading immune cell plasticity and differentiation. We have demonstrated that MDSCs in the brain microenvironment respond to the neurotransmitter serotonin, upregulate the serotonergic receptor, HTR2B, resulting in increase pNF-κB and its associated signaling genes (IL-6, IL-1B, COX2, CXCL2, NOS2). Furthermore, HTR2B knockdown in MDSCs alters downregulates expression of pNF-κB signaling genes. Additionally, MDSCs in this environment support tumor cell proliferation while hindering their acquisition of neuronal traits. A better understanding of the role of HTR2B in brain metastasis may allow us to develop new treatment strategies for patients of this devastating disease.